Ultra-miniature dual-wavelength spatial frequency domain imaging for micro-endoscopy

There is a need for a cost-effective, quantitative imaging tool that can be deployed endoscopically to better detect early stage gastrointestinal cancers. Spatial frequency domain imaging (SFDI) is a low-cost imaging technique that produces near-real time, quantitative maps of absorption and reduced scattering coefficients, but most implementations are bulky and suitable only for use outside the body. We present an ultra-miniature SFDI system comprised of an optical fiber array (diameter 0.125 mm) and a micro camera (1 x 1 mm package) displacing conventionally bulky components, in particular the projector. The prototype has outer diameter 3 mm, but the individual components dimensions could permit future packaging to < 1.5 mm diameter. We develop a phase-tracking algorithm to rapidly extract images with fringe projections at 3 equispaced phase shifts in order to perform SFDI demodulation. To validate performance, we first demonstrate comparable recovery of quantitative optical properties between our ultra-miniature system and a conventional bench-top SFDI system with agreement of 15% and 6% for absorption and reduced scattering respectively. Next, we demonstrate imaging of absorption and reduced scattering of tissue-mimicking phantoms providing enhanced contrast between simulated tissue types (healthy and tumour), done simultaneously at wavelengths of 515 nm and 660 nm. This device shows promise as a cost-effective, quantitative imaging tool to detect variations in optical absorption and scattering as indicators of cancer.Comment: 26 Pages, 7 Figure

Phthalide annulation: the synthesis of kalafungin, pachybasin and chrysophanol

The anions of %cyano- or 3-(pheny1thio)phthalide react with Michael acceptors to afford functionalized naphthydroquinones in good yield. The cyano and phenylthio groups function both as activating groups and as leaving groups. An alternative involves the use of protected o-(carboxymethy1)cyanohydrins. The use of phthalide anions in synthesis is exemplified by total syntheses of kalafungin, pachybasin, and chrysophanol. This methodolgy consititutes a direct and regiospecific approach to polycyclic systems

Ultra-miniaturised spatial frequency domain imaging for improved early detection of gastrointestinal cancers

The low five year-survival rates for gastrointestinal cancers evidences a strong clinical need to improve their early detection. Current imaging methods for early detection are expensive and rely on white light imaging which lacks sufficient contrast to spot a wide range of potential tumours. Changes in absorption and reduced scattering coefficients can be linked to pre-cancerous abnormalities, such as Barrett’s Oesophagus, and invasive squamous cell carcinoma, in the oesophagus. Spatial Frequency Domain Imaging (SFDI) is a low-cost imaging technique from which quantitative maps of absorption and reduced scattering coefficients may be obtained using structured illumination. We have developed a clinically translatable, ultra-miniaturised SFDI system using optical fibers (0.125 mm diameter) to project structured illumination and a miniature camera (< 1 mm diameter) to capture the pattern response for a sample under test. The total package could therefore be made < 1.1mm diameter, representing, to the best of our knowledge, the smallest full SFDI probe achieved to date. We have demonstrated recovery of absorption and reduced scattering maps with our system for tissue mimicking co-polymer in oil phantoms of biologically relevant absorption and scattering properties. This technology represents a first step towards a less-invasive, cost-effective device which produces close to real-time absorption and reduced scattering maps for improved in vivo disease detection of the gastrointestinal tract

Multimode bolometer development for the PIXIE instrument

The Primordial Inflation Explorer (PIXIE) is an Explorer-class mission concept designed to measure the polarization and absolute intensity of the cosmic microwave background. In the following, we report on the design, fabrication, and performance of the multimode polarization-sensitive bolometers for PIXIE, which are based on silicon thermistors. In particular we focus on several recent advances in the detector design, including the implementation of a scheme to greatly raise the frequencies of the internal vibrational modes of the large-area, low-mass optical absorber structure consisting of a grid of micromachined, ion-implanted silicon wires. With $\sim30$ times the absorbing area of the spider-web bolometers used by Planck, the tensioning scheme enables the PIXIE bolometers to be robust in the vibrational and acoustic environment at launch of the space mission. More generally, it could be used to reduce microphonic sensitivity in other types of low temperature detectors. We also report on the performance of the PIXIE bolometers in a dark cryogenic environment.Comment: 10 pages, 7 figure

Simulating medical applications of tissue optical property and shape imaging using open-source ray tracing software

Oesophageal cancer and colon cancer have five year survival rates of 15% and 63% respectively. These low survival rates are due in part to poor early detection during endoscopic screening, with conventional endoscopes providing insufficient information about tissue properties to spot a wide range of potential tumours. Improving early detection of gastrointestinal cancers would dramatically increase their five year survival rates. Spatial Frequency Domain Imaging (SFDI) is a low-cost imaging technique that can measure absorption, scattering and shape as potential indicators of cancer. Specific absorption and scattering properties are known to be linked to malignancy in the oesophagus, and shape is an important indicator in colon cancer. Though a range of research and commercial SFDI systems have been developed, adapting these for in vivo clinical application is challenging due to constraints imposed by miniaturisation, sample geometry and illumination conditions. To facilitate design of novel SFDI systems under such constraints, we have developed a model of an SFDI imaging system built on the open-source 3D modelling software Blender. Using Blender’s Cycles ray-tracing engine, we are able to simulate a range of different scattering and absorption coefficients for a number of different imaging configurations, sample geometries and illumination patterns. Using established processing algorithms, we show we can recover maps of absorption, scattering and shape in a range of simulated ex vivo and in vivo imaging geometries with relevance to clinical detection of tumours. Our system enables accessible exploration of different optical configurations and realistic illumination conditions that will inform future design of compact, low-cost instruments

Phaselocked patterns and amplitude death in a ring of delay coupled limit cycle oscillators

We study the existence and stability of phaselocked patterns and amplitude death states in a closed chain of delay coupled identical limit cycle oscillators that are near a supercritical Hopf bifurcation. The coupling is limited to nearest neighbors and is linear. We analyze a model set of discrete dynamical equations using the method of plane waves. The resultant dispersion relation, which is valid for any arbitrary number of oscillators, displays important differences from similar relations obtained from continuum models. We discuss the general characteristics of the equilibrium states including their dependencies on various system parameters. We next carry out a detailed linear stability investigation of these states in order to delineate their actual existence regions and to determine their parametric dependence on time delay. Time delay is found to expand the range of possible phaselocked patterns and to contribute favorably toward their stability. The amplitude death state is studied in the parameter space of time delay and coupling strength. It is shown that death island regions can exist for any number of oscillators N in the presence of finite time delay. A particularly interesting result is that the size of an island is independent of N when N is even but is a decreasing function of N when N is odd.Comment: 23 pages, 12 figures (3 of the figures in PNG format, separately from TeX); minor additions; typos correcte

Subduction Initiation Recorded in the Dadeville Complex of Alabama and Georgia, Southeastern United States

The Dadeville Complex of Alabama and Georgia (southeastern United States) represents the largest suite of exposed mafic-ultramafic rocks in the southern Appalachians. Due to poor preservation, chemical alteration, and tectonic reworking, a specific tectonic origin for the Dadeville Complex has been difficult to deduce. We obtained new whole-rock and mineral geochemistry coupled with zircon U-Pb geochronology to investigate the magmatic and metamorphic processes recorded by the Dadeville Complex, as well as the timing of these processes. Our data reveal an up-stratigraphic evolution in the geochemistry of the volcanic rocks, from forearc basalts to boninites. Our new U-Pb zircon crystallization data—obtained from three amphibolite samples—place the timing of forearc/protoarc volcanism no later than ca. 467 Ma. New thermobarometry suggests that the Dadeville Complex rocks subsequently experienced deep, high-grade metamorphism, at pressure-temperature conditions of \u3e7 kbar and \u3e760 °C. The data presented here support a model for formation of the Dadeville Complex in the forearc region of a subduction zone during subduction initiation and protoarc development, followed by deep burial/underthrusting of the complex during orogenesis

Maspin is a deoxycholate-inducible, anti-apoptotic stress-response protein differentially expressed during colon carcinogenesis

Increased maspin expression in the colon is related to colon cancer risk and patient survival. Maspin is induced by the hydrophobic bile acid, deoxycholate (DOC), which is an endogenous carcinogen and inducer of oxidative stress and DNA damage in the colon. Persistent exposure of colon epithelial cells, in vitro, to high physiologic levels of DOC results in increased constitutive levels of maspin protein expression associated with the development of apoptosis resistance. When an apoptosis-resistant colon epithelial cell line (HCT-116RC) developed in the authors’ laboratory was treated with a maspin-specific siRNA probe, there was a statistically significant increase in apoptosis compared to treatment with an siRNA control probe. These results indicate, for the first time, that maspin is an anti-apoptotic protein in the colon. Immunohistochemical evaluation of maspin expression in human colonic epithelial cells during sporadic colon carcinogenesis (131 human tissues evaluated) indicated a statistically significant increase in maspin protein expression beginning at the polyp stage of carcinogenesis. There was no statistically significant difference in maspin expression between hyperplastic/adenomatous polyps and colonic adenocarcinomas. The absence of “field defects” in the non-neoplastic colonic mucosa of patients with colonic neoplasia indicates that maspin may drive the growth of tumors, in part, through its anti-apoptotic function

Identification of novel therapeutics for complex diseases from genome-wide association data

Background: Human genome sequencing has enabled the association of phenotypes with genetic loci, but our ability to effectively translate this data to the clinic has not kept pace. Over the past 60 years, pharmaceutical companies have successfully demonstrated the safety and efficacy of over 1,200 novel therapeutic drugs via costly clinical studies. While this process must continue, better use can be made of the existing valuable data. In silico tools such as candidate gene prediction systems allow rapid identification of disease genes by identifying the most probable candidate genes linked to genetic markers of the disease or phenotype under investigation. Integration of drug-target data with candidate gene prediction systems can identify novel phenotypes which may benefit from current therapeutics. Such a drug repositioning tool can save valuable time and money spent on preclinical studies and phase I clinical trials. Methods. We previously used Gentrepid (http://www.gentrepid.org) as a platform to predict 1,497 candidate genes for the seven complex diseases considered in the Wellcome Trust Case-Control Consortium genome-wide association study; namely Type 2 Diabetes, Bipolar Disorder, Crohn's Disease, Hypertension, Type 1 Diabetes, Coronary Artery Disease and Rheumatoid Arthritis. Here, we adopted a simple approach to integrate drug data from three publicly available drug databases: the Therapeutic Target Database, the Pharmacogenomics Knowledgebase and DrugBank; with candidate gene predictions from Gentrepid at the systems level. Results: Using the publicly available drug databases as sources of drug-target association data, we identified a total of 428 candidate genes as novel therapeutic targets for the seven phenotypes of interest, and 2,130 drugs feasible for repositioning against the predicted novel targets. Conclusions: By integrating genetic, bioinformatic and drug data, we have demonstrated that currently available drugs may be repositioned as novel therapeutics for the seven diseases studied here, quickly taking advantage of prior work in pharmaceutics to translate ground-breaking results in genetics to clinical treatments. © 2014 Grover et al.; licensee BioMed Central Ltd